Yu Liping, Hajduk Philip J, Mack Jamey, Olejniczak Edward T
Pharmaceutical Discovery Division, GPRD, Abbott Laboratories, Abbott Park, IL 60064-6098, USA.
J Biomol NMR. 2006 Apr;34(4):221-7. doi: 10.1007/s10858-006-0005-y.
Fluorine atoms are often incorporated into drug molecules as part of the lead optimization process in order to improve affinity or modify undesirable metabolic and pharmacokinetic profiles. From an NMR perspective, the abundance of fluorinated drug leads provides an exploitable niche for structural studies using 19F NMR in the drug discovery process. As 19F has no interfering background signal from biological sources, 19F NMR studies of fluorinated drugs bound to their protein receptors can yield easily interpretable and unambiguous structural constraints. 19F can also be selectively incorporated into proteins to obtain additional constraints for structural studies. Despite these advantages, 19F NMR has rarely been exploited for structural studies due to its broad lines in macromolecules and their ligand complexes, leading to weak signals in 1H/19F heteronuclear NOE experiments. Here we demonstrate several different experimental strategies that use 19F NMR to obtain ligand-protein structural constraints for ligands bound to the anti-apoptotic protein Bcl-xL, a drug target for anti-cancer therapy. These examples indicate the applicability of these methods to typical structural problems encountered in the drug development process.
在先导化合物优化过程中，氟原子常被引入药物分子中，以提高亲和力或改善不良的代谢和药代动力学特征。从核磁共振（NMR）的角度来看，大量含氟药物先导化合物为药物发现过程中使用19F NMR进行结构研究提供了一个可利用的领域。由于19F没有来自生物源的干扰背景信号，对与其蛋白质受体结合的含氟药物进行19F NMR研究可以产生易于解释且明确的结构限制。19F也可以选择性地掺入蛋白质中，以获得用于结构研究的额外限制。尽管有这些优点，但由于19F在大分子及其配体复合物中的谱线较宽，导致1H/19F异核NOE实验中的信号较弱，19F NMR很少被用于结构研究。在这里，我们展示了几种不同的实验策略，这些策略使用19F NMR来获得与抗凋亡蛋白Bcl-xL（一种抗癌治疗的药物靶点）结合的配体的配体-蛋白质结构限制。这些例子表明了这些方法在药物开发过程中遇到的典型结构问题上的适用性。
